Sekar Kathiresan (Verve)

Sekar Kathire­san show­cas­es his­toric mon­key da­ta in hunt for a once-and-done gene edit­ing ap­proach to pre­vent heart at­tacks

In a first for CRISPR — a field that’s seen quite a few his­toric moves in the past cou­ple of years — sci­en­tists have slashed cho­les­terol and lipid lev­els in mon­keys us­ing a tech­nique known as base edit­ing, gen­er­at­ing cru­cial proof-of-con­cept for both the biotech be­hind the ex­per­i­ment and a key part­ner.

Verve Ther­a­peu­tics de­signed two sim­i­lar ex­per­i­ments to test whether they can re­pro­duce pro­tec­tive mu­ta­tions in a pair of genes us­ing an ade­nine base ed­i­tor, which pre­cise­ly al­ters a cho­sen A to a G in the genome. CEO and co-founder Sekar Kathire­san pre­sent­ed the re­sults at a vir­tu­al keynote for the In­ter­na­tion­al So­ci­ety for Stem Cell Re­search over the week­end.

The base ed­i­tors ap­peared to have es­sen­tial­ly turned off genes, shut­ting down pro­duc­tion of cor­re­spond­ing pro­teins. That trans­lat­ed to a 60% drop in LDL with the PC­SK9 ther­a­py and a 64% plunge in triglyc­erides on the ANGPTL3 treat­ment.

When it comes to low­er­ing the col­lo­qui­al bad cho­les­terol, “60% is on par if not bet­ter than any oth­er treat­ment out there,” Kathire­san told End­points News just af­ter his pre­sen­ta­tion.

These re­sults are the cul­mi­na­tion of Kathis­er­an’s decades-long search for ge­net­ic clues for solv­ing coro­nary heart dis­ease, the lead­ing cause of death in the world. While di­rec­tor of the Cen­ter for Ge­nom­ic Med­i­cine at Mass­a­chu­setts Gen­er­al Hos­pi­tal and the Car­dio­vas­cu­lar Dis­ease Ini­tia­tive at the Broad In­sti­tute, he and col­leagues had iden­ti­fied eight genes that har­bor rare mu­ta­tions as­so­ci­at­ed with re­sis­tance to my­ocar­dial in­farc­tion. Af­ter show­ing in mice that they could ad­min­is­ter a one-time treat­ment for per­ma­nent low­er­ing of cho­les­terol, he left acad­e­mia to work on bring­ing it to hu­mans full-time.

There is, of course, still a long way to go. But Kathire­san be­lieves the new da­ta have lit up Verve’s path to the clin­ic.

They are still choos­ing be­tween the PC­SK9 and ANGPTL3 pro­grams as their lead can­di­date. Once they do — the dead­line will be the end of the year — an IND for pa­tients ge­net­i­cal­ly pre­dis­posed to high risk of heart at­tack is in sight for 2022.

Both pro­grams demon­strat­ed dra­mat­ic re­duc­tions in the tar­get pro­tein, cut­ting 89% of PC­SK9 and 95% of ANGPTL3 from the blood­stream. With the study lim­it­ed to two weeks, though, the dura­bil­i­ty ques­tions loomed large dur­ing the Q&A.

“We have en­cour­ag­ing da­ta out to sev­er­al months now,” Kathire­san said, ex­press­ing con­fi­dence that the edit­ing will be sta­ble long-term.

The rate of DNA reached 67% of the liv­er for PC­SK9 and 60% for ANGPTL3 which, Kathis­er­an point­ed out, rep­re­sents the ma­jor­i­ty of he­pa­to­cytes as around 30% of the liv­er is sup­port­ing tis­sue. Get­ting to not just ma­ture he­pa­to­cytes but al­so stem cells would be cru­cial. In pre­vi­ous re­search by oth­er groups, sci­en­tists have ob­served con­tin­ued edit­ing in mice cells even when they chop out parts of the liv­er and let it re­gen­er­ate.

Con­sid­er­ing the base ed­i­tors were de­ployed in vi­vo, safe­ty was al­so para­mount. Verve re­port­ed no off-tar­get ed­its in the 108 sites mea­sured — ow­ing, Kathire­san said, to the tech­nol­o­gy they have li­censed from Beam Ther­a­peu­tics.

Un­like the first gen­er­a­tion of CRISPR edit­ing, base edit­ing doesn’t snip at the site Cas9 brings it to; rather, through an en­zyme, it con­verts one base to an­oth­er chem­i­cal­ly.

“So it’s kind of in­ge­nious be­cause it us­es the GPS lo­cal­iza­tion fea­ture of Cas9, but it doesn’t use the dou­ble-strand break fea­ture of Cas9,” he said.

Apart from the mR­NA that forms the ed­i­tor, every Verve ther­a­py al­so con­sists of a guide RNA — picked out from hun­dreds — di­rect­ing the ma­chin­ery to the de­sired spot, all en­cap­su­lat­ed in a lipid nanopar­ti­cle en­gi­neered in col­lab­o­ra­tion with Van­cou­ver-based Acuitas.

De­liv­er­ing with lipid nanopar­ti­cles in­stead of a vi­ral vec­tor is a de­lib­er­ate choice.

“We need to get in, get the ed­i­tor and the guide RNA, get the edit­ing to hap­pen and then every­thing to go away as quick­ly as pos­si­ble,” Kathire­san said, “be­cause the longer the liv­er is ex­posed to the edit­ing ma­chin­ery, the more like­ly you are to get off-tar­get ef­fects. and lipid nanopar­ti­cles al­low de­liv­ery and then res­o­lu­tion of the process with­in a cou­ple of days.”

Al­so de­lib­er­ate is their de­ci­sion to part­ner wide­ly and as­sem­ble — not in­vent — all the tools that might aid their work. Base ed­i­tors aren’t go­ing to cov­er the full spec­trum of pos­si­ble and nec­es­sary changes as Kathire­san and his team go down their pri­or­i­tized list of eight genes. But they are tak­ing it one step at a time.

Donald and Melania Trump watch the smoke of fireworks from the South Lawn of the White House on July 4, 2020 (via Getty)

Which drug de­vel­op­ers of­fer Trump a quick, game-chang­ing ‘so­lu­tion’ as the pan­dem­ic roars back? Eli Lil­ly and Ab­Cellera look to break out of the pack

We are unleashing our nation’s scientific brilliance and will likely have a therapeutic and/or vaccine solution long before the end of the year.

— Donald Trump, July 4

Next week administration officials plan to promote a new study they say shows promising results on therapeutics, the officials said. They wouldn’t describe the study in any further detail because, they said, its disclosure would be “market-moving.”

— NBC News, July 3

Something’s cooking. And it’s not just July 4 leftovers involving stale buns and uneaten hot dogs.

Over the long weekend observers picked up signs that the focus in the Trump administration may swiftly shift from the bright spotlight on vaccines being promised this fall, around the time of the election, to include drugs that could possibly keep patients out of the hospital and take the political sting out of the soaring Covid-19 numbers causing embarrassment in states that swiftly reopened — as Trump cheered along.

So far, Gilead has been the chief beneficiary of the drive on drugs, swiftly offering enough early data to get remdesivir an emergency authorization and into the hands of the US government. But their drug, while helpful in cutting stays, is known for a limited, modest effect. And that won’t tamp down on the hurricane of criticism that’s been tearing at the White House, and buffeting the president’s most stalwart core defenders as the economy suffers.

We’ve had positive early-stage vaccine data, most recently from Pfizer and BioNTech, playing catchup on an mRNA race led by Moderna — where every little sign of potential trouble is magnified into a lethal threat, just as every advance excites a frenzy of support. But that race still has months to play out, with more Phase I data due ahead of the mid-stage numbers looming ahead. A vaccine may not be available in large enough quantities until well into 2021, which is still wildly ambitious.

So what about a drug solution?

Trump’s initial support for a panacea focused on hydroxychloroquine. But that fizzled in the face of data underscoring its ineffectiveness — killing trials that aren’t likely to be restarted because of a recent population-based study offering some support. And there are a number of existing drugs being repurposed to see how they help hospitalized patients.

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Sec­ond death trig­gers hold on Astel­las' $3B gene ther­a­py biotech's lead pro­gram, rais­ing fresh con­cerns about AAV

Seven months after Astellas shelled out $3 billion to acquire the gene therapy player Audentes, the biotech company’s lead program has been put on hold following the death of 2 patients taking a high dose of their treatment. And there was another serious adverse event recorded in the study as well, with a total of 3 “older” patients in the study affected.

The incidents are derailing plans to file for a near-term approval, which had been expected right about now.

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George Yancopoulos (Regeneron)

UP­DAT­ED: Re­gen­eron co-founder George Yan­copou­los of­fers a com­bat­ive de­fense of the po­lice at a high school com­mence­ment. It didn’t go well

Typically, the commencement speech at Yorktown Central School District in Westchester — like most high schools — is an opportunity to encourage students to face the future with confidence and hope. Regeneron president and co-founder George Yancopoulos, though, went a different route.

In a fiery speech, the outspoken billionaire defended the police against the “prejudice and bias against law enforcement” that has erupted around the country in street protests from coast to coast. And for many who attended the commencement, Yancopoulos struck the wrong note at the wrong time, especially when he combatively challenged someone for interrupting his speech with a honk for “another act of cowardness.”

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Elias Zerhouni (Photo by Vincent Isore/IP3/Getty Images)

Elias Zer­houni dis­cuss­es ‘am­a­teur hour’ in DC, the de­struc­tion of in­fec­tious dis­ease R&D and how we need to prep for the next time

Elias Zerhouni favors blunt talk, and in a recent discussion with NPR, the ex-Sanofi R&D and ex-NIH chief had some tough points to make regarding the pandemic response.

Rather than interpret them, I thought it would be best to provide snippets straight from the interview.

On the Trump administration response:

It was basically amateur hour. There is no central concept of operations for preparedness, for pandemics, period. This administration doesn’t want to or has no concept of what it takes to protect the American people and the world because it is codependent. You can’t close your borders and say, “OK, we’re going to be safe.” You’re not going to be able to do that in this world. So it’s a lack of vision, basically just a lack of understanding, of what it takes to protect the American people.

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Tesla and SpaceX founder Elon Musk gestures to the audience after being recognized by President Trump following the successful launch of a Falcon 9 rocket at the Kennedy Space Center. (via Getty Images)

Tes­la chief Elon Musk teams up with Covid-19 play­er Cure­Vac to build 'R­NA mi­cro­fac­to­ries'

Elon Musk has joined the global tech crusade now underway to revolutionize vaccine manufacturing — now aimed at delivering billions of doses of a new mRNA vaccine to fight Covid-19. And he’s cutting right to the front.

In a late-night tweet Wednesday, the Tesla chief announced:

Tesla, as a side project, is building RNA microfactories for CureVac & possibly others.

That’s not a lot to go on. But the tweet comes a year after Tesla’s German division in Grohmann and CureVac filed a patent on a “bioreactor for RNA in vitro transcription, a method for RNA in vitro transcription, a module for transcribing DNA into RNA and an automated apparatus for RNA manufacturing.” CureVac, in the meantime, has discussed a variety of plans to build microfactories that can speed up the whole process for a global supply chain.

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Paul Tesar (Convelo Therapeutics)

Io­n­is, lead­ing MS re­searcher throw an­ti­sense at a new type of brain cells

No matter how many molecules he threw at them, Paul Tesar couldn’t get the brain cells to survive. Or he got them to survive, but then — to everyone’s bafflement — they still couldn’t do what they were supposed to.

Tesar, a professor of innovative therapeutics at Case Western University, had spent years building stem cell models for multiple sclerosis, growing brain organoids in dishes and then seeing what small molecules restored myelin production. Now he was trying to do the same for other myelin diseases, particularly an ultra-rare genetic condition called Pelizaeus-Merzbacher disease, where a single mutation leads to the death of the myelin-producing neurons, called oligodendrocytes, and can kill patients in infancy.

Pfiz­er shares surge on pos­i­tive im­pact of their mR­NA Covid-19 vac­cine — part­nered with BioN­Tech — in an ear­ly-stage study

Pfizer and their partners at the mRNA specialist BioNTech have published the first glimpse of biomarker data from an early-stage study spotlighting the “robust immunogenicity” triggered by their Covid-19 vaccine, which is one of the leaders in the race to vanquish the global pandemic.

Researchers selected 45 healthy volunteers 18-55 years of age for the study. They were randomized to receive 2 doses, separated by 21 days, of 10 µg, 30 µg, or 100 µg of BNT162b1, “a lipid nanoparticle-formulated, nucleoside-modified, mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein RBD.” Their responses were compared against the effect of a natural, presumably protective defense offered by a regular infection.

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An ex­pe­ri­enced biotech is stitched to­geth­er from transpa­cif­ic parts, with 265 staffers and a fo­cus on ‘new bi­ol­o­gy’

Over the past few years, different teams at a pair of US-based biotechs and in labs in Japan have labored to piece together a group of cancer drug programs, sharing a single corporate umbrella with research colleagues in Japan. But now their far-flung operations have been knit together into a single unit, creating a pipeline with 10 cancer drug development programs — going from early-stage right into Phase III — and a host of discovery projects managed by a collective staff of some 265 people.

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New stan­dard of care? FDA hands Pfiz­er, Mer­ck KGaA an OK for Baven­cio in blad­der can­cer

The breakthrough therapy designation Pfizer and Merck KGaA notched for Bavencio in bladder cancer has quickly paved way for a full approval.

The PD-L1 drug is now sanctioned as a first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma, applicable in cases where cancer hasn’t progressed after platinum-containing chemotherapy.

Petros Grivas, the principal investigator of the supporting Phase III JAVELIN Bladder 100, called the approval “one of the most significant advances in the treatment paradigm in this setting in 30 years.”